Effects of Soluble Guanylyl Cyclase Activation on Skeletal Muscle Microcirculatory Oxygen Exchange in Rats with Heart Failure with Reduced Ejection Fraction

Introduction: In heart failure (HF), nitric oxide (NO) pathway dysfunction impairs muscle arteriolar vasodilation and thus capillary hemodynamics, contributing to impaired oxygen uptake (VO2) kinetics. Due to poor prognosis and enhanced muscle fatigability following myocardial infarction, new treatment options are pursued heavily. To target downstream effects of NO directly, soluble guanyl cyclase (sGC) activators were developed. This investigation tested the hypotheses that chronic administration of a sGC activator would increase the O2 delivery (Q̇O2)-to-O2 utilization (VO2) ratio in the skeletal muscle interstitial space (PO2is) of HF rats during twitch contractions due, in part, to increases in red blood cell (RBC) flux (f[subscript]RBC) and hematocrit (Hct[subscript]cap). Furthermore, we investigated whether exogenous NO (sodium nitroprusside, SNP) superfusion in addition to sGC activator would improve the QO2-VO2 ratio and capillary hemodynamics further. Methods: HF was induced in adult male Sprague-Dawley (3-4 mo. old) rats via myocardial infarction (MI). Following ~3 weeks of HF progression, 0.3 mg/kg sGC activator in 1 ml vehicle (10% Transcutol, 20% Cremophor, Sigma Aldrich, St. Louis, MO, and 70% water) was administered via oral gavage twice a day (HF + sGC; n =10) for 5 days prior to phosphorescence quenching (PO2is, in contracting muscle) and intravital microscopy (rest) measurements in the spinotrapezius muscle. The control heart failure group (HF; n = 9) received vehicle only. Intravital microscopy measured f[subscript]RBC, V[subscript]RBC, and Hct[subscript]cap under resting conditions. Results: Intravital microscopy revealed greater increases in Hct[subscript]cap (+16 ± 1 vs 10 ± 1%) of HF + sGC vs HF, respectively. Interestingly, f[subscript]RBC and V[subscript]RBC respectively, were both increased in HF + sGC vs HF (70 ± 9 vs 25 ± 8 RBC/s) and (490 ± 43 vs 226 ± 35 [mu]m/s) (P